A Formative Evaluation of the Bloomington-Normal Entrepreneurial Ecosystem

This study serves as a formative evaluation of the Bloomington-Normal-McLean County, IL region’s entrepreneurial ecosystem, which the development thereof is a tactical strategy outlined in the recently created Bloomington-Normal economic development plan (also known as BN Advantage). An entrepreneurial ecosystem is a network comprising of entrepreneurs, supporting organizations and entities such as investors, governments, universities and various other organizations with a focus on economic development. Vibrant entrepreneurial ecosystems strengthen local entrepreneurial capacity, which then spurs economic development through job creation and growth, economic diversity and increasing a region’s competitive advantage. The methodology of this study involved combining qualitative and quantitative data to best understand the strengths, weakness, opportunities, threats and overall vibrancy of the ecosystem. This study aims to provide the Bloomington-Normal-McLean Co., IL community with a snapshot of the local entrepreneurial ecosystem, and to offer evidence-based approaches which the community can use to strengthen the entrepreneurial ecosystem in the future

Designing Innovative Corporate Water Risk Management Strategies from an Ecosystem Services Perspective

In January of 2012, we teamed up with representatives from the sustainability department at The Dow Chemical Company with the goal of creating a viable, creative solution that would advance The Company’s efforts to address the risk associated with freshwater scarcity. With uncertainty surrounding the impacts of climate change and other environmental threats, it is becoming increasingly important for corporations to fully understand and incorporate the value of the benefits nature provides into strategic decisions. The focal ecosystem service of our project was freshwater provisioning. Freshwater is critical to life and a key ingredient to many economic activities, such as power generation, agriculture and industrial processes. Water scarcity is of particular interest to Dow, given that 20 percent of The Company’s global production comes from the Freeport, Texas facility on the water-stressed Brazos River.1 Water is used as both an input to production and a coolant for electricity generation. The growing uncertainty around the future supply of water could threaten continuity of operations at Freeport and other increasingly water-stressed sites.2 After surveying the common responses to water scarcity, the team broke down these various solutions into three categories: technology-based, policy-based, or management-based. Management-based solutions, defined here as responses developed within the organization that involve changes to internal policies and processes, were determined to hold the most promise for creating a robust, organization-wide solution for potential freshwater scarcity. We conducted a broad search to identify creative management responses by a variety of institutions to natural resource challenges and selected ten types of responses, referred to as “analogues,” exemplified through one or more specific case studies. We then considered how each analogue could be adapted to the unique characteristics of water and the context of the corporate setting. Our five-step methodology including the following: 1) develop criteria for evaluating the analogue cases; 2) identify and evaluate the cases against those criteria; 3) deconstruct each case to determine the mechanisms driving effective resource management decisions; 4) adapt those mechanisms to the freshwater challenge; and 5) as necessary, adapt those mechanisms to the corporate context. We then evaluated the purpose, strengths and weaknesses of each analogue and identified common enabling conditions, benefits and limitations. After considering commonalities, we compared and mapped out unique benefits and limitations for application to freshwater scarcity in the corporate context. 5 The analysis was used to provide a strategic recommendation for addressing water scarcity at The Dow Chemical Company. Building from the analogue benefits and limitations outlined above, we were able to identify a way in which multiple analogues could be used in a complementary manner to achieve Dow’s goals within its particular organizational context. The initial proposal incorporated mechanisms from carbon taxing, infrastructure portfolio standard, and revolving fund analogues. These analogues provided mechanisms to generate and allocate capital by placing a tax on water use, with fee revenue dedicated to a revolving fund. This revolving fund financed water projects prioritized through the portfolio standard. Through further iterations and discussions with environmental and finance staff at Dow, we further refined our proposal to combine elements from two analogues– infrastructure portfolio standards and revolving funds – with a balanced scorecard approach to performance evaluation. In this case, capital is allocated internally to a fund that is used to finance projects prioritized by the portfolio standard. Projects are evaluated and reviewed for continued funding based on a scorecard that considers both financial return and other beneficial outcomes. This recommended strategy is sensitive to the financial realities and processes within Dow and is flexible to allow for the varied operational and policy contexts in which Dow faces freshwater scarcity challenges around the globe. Further, it addresses the desire of The Company to frame and address sustainability holistically, while still using freshwater scarcity as a focal challenge within the new effort. We believe that the analogues analyzed in this report can be combined in multiple ways to overcome a broad range of sustainability challenges. The analysis is designed to illuminate the potential applications of the mechanisms underlying each analogue. We hope that it inspires readers to think more broadly and creatively about effective options for responding to natural resource challenges.Master of ScienceNatural Resources and EnvironmentUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/97548/1/Designing Innovative Corp Water Risk mgmt Strategies 2013.pd

Water Your Opinions: A Social Assessment of the Lake Bloomington and Lake Evergreen Watersheds

The purpose of this report is to better understand the knowledge of and attitudes of residents towards water resources in the McLean County area. The assessment consisted of nine key informant interviews and two community focus groups with local residents who have a vested interest in and specific knowledge about these water resources. This is one part of a larger assessment in partnership with the McLean County Soil and Water Conservation District (MCSWCD). The results of this assessment will help to inform specific questions to be used in a residential household survey in spring 2015. The survey will be used to gain a better insight into the public’s knowledge and attitudes towards water resources in McLean County. This will enable MCSWCD and water managers to strategically plan for future water resources in McLean County. A number of other findings, limitations of the assessment, and recommendations and future research are discussed

Cell wall damage reveals spatial flexibility in peptidoglycan synthesis and a non-redundant role for RodA in mycobacteria [preprint]

Cell wall peptidoglycan is a heteropolymeric mesh that protects the bacteria from internal turgor and external insults. In many rod-shaped bacteria, peptidoglycan synthesis for normal growth is achieved by two distinct pathways: the Rod complex, comprised of MreB, RodA and a cognate class B PBP, and the class A PBPs. In contrast to laterally-growing bacteria, pole-growing mycobacteria do not encode an MreB homolog and do not require SEDS protein RodA for in vitro growth. However, RodA contributes to survival of Mycobacterium tuberculosis in some infection models, suggesting that the protein could have a stress-dependent role in maintaining cell wall integrity. Under basal conditions, we find here that the subcellular distribution of RodA largely overlaps with that of the aPBP PonA1, and that both RodA and the aPBPs promote polar peptidoglycan assembly. Upon cell wall damage, RodA fortifies M. smegmatis against lysis and, unlike aPBPs, contributes to a shift in peptidoglycan assembly from the poles to the sidewall. Neither RodA nor PonA1 relocalize; instead, the redistribution of nascent cell wall parallels that of peptidoglycan precursor synthase MurG. Our results support a model in which mycobacteria balance polar growth and cell-wide repair via spatial flexibility in precursor synthesis and extracellular insertion. Importance Peptidoglycan synthesis is a highly successful target for antibiotics. The pathway has been extensively studied in model organisms under laboratory-optimized conditions. In natural environments, bacteria are frequently under attack. Moreover the vast majority of bacterial species are unlikely to fit a single paradigm because of differences in growth mode and/or envelope structure. Studying cell wall synthesis under non-optimal conditions and in non-standard species may improve our understanding of pathway function and suggest new inhibition strategies. Mycobacterium smegmatis, a relative of several notorious human and animal pathogens, has an unusual polar growth mode and multi-layered envelope. In this work we challenged M. smegmatis with cell wall-damaging enzymes to characterize the roles of cell wall-building enzymes when the bacterium is under attack

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Table_1_Tetraploidy accelerates adaptation under drug selection in a fungal pathogen.docx

Baseline ploidy significantly impacts evolutionary trajectories and, specifically, tetraploidy is associated with higher rates of adaptation relative to haploidy and diploidy. While the majority of experimental evolution studies investigating ploidy use the budding yeast Saccharomyces cerivisiae, the fungal pathogen Candida albicans is a powerful system to investigate ploidy dynamics, particularly in the context of acquiring antifungal drug resistance. C. albicans laboratory and clinical strains are predominantly diploid, but have been isolated as haploid and polyploid. Here, we evolved diploid and tetraploid C. albicans for ~60 days in the antifungal drug caspofungin. Tetraploid-evolved lines adapted faster than diploid-evolved lines and reached higher levels of caspofungin resistance. While diploid-evolved lines generally maintained their initial genome size, tetraploid-evolved lines rapidly underwent genome-size reductions and did so prior to caspofungin adaptation. While clinical resistance was largely due to mutations in FKS1, these mutations were caused by substitutions in diploid, and indels in tetraploid isolates. Furthermore, fitness costs in the absence of drug selection were significantly less in tetraploid-evolved lines compared to the diploid-evolved lines. Taken together, this work supports a model of adaptation in which the tetraploid state is transient but its ability to rapidly transition ploidy states improves adaptive outcomes and may drive drug resistance in fungal pathogens.</p